tbuckley/cabot-search huggingface dataset:
P036: Detection of recurrent somatic variants in cell-free DNA as a tool for disease monitoring in Hodgkin lymphoma
Authors: Jan Grohmann, Alexandra Kredatusova, Jana Navratilova, Veronika Hanackova, Helena Urbankova, Vit Prochazka, Tomas Papajik
Journal: HemaSphere (2022)

Figure 1: MRD monitoring in patient PA-1971 by dPCR using STAT6 (p.N417Y) A major challenge in the health care management of HL is finding optimal balance between treatment efficacy and risk of toxicity. Nowadays there is no reliable and precise tool for evaluation of treatment response and MRD monitoring due to scarce presence and difficult availability of neoplastic cells. The cell-free DNA (cfDNA) in HL reflects its mutational profile and could be source for genotyping assays. We developed a specific NGS panel for analysis of 13 genes involved in pathogenesis of HL. Selected variants detected by NGS were subsequently used for MRD monitoring by droplet PCR (dPCR). Our cohort consisted of 48 pts: 20 females/28 males; median age of dg 39.5 years. Histological subtypes: 28 pts (58%) NSCHL; 14 pts (29%) MCCHL; 1 pt (2%) NLPHL; 1 pt (2%) LRCHL (4 pts not determined). Forty four samples were obtained at dg/ 4 in relapse. CfDNA was extracted from peripheral blood plasma using QiaAmp Circulating nucleic acid kit (Qiagen). Specific NGS panel covering coding sequences (including UTRs) of 13 selected genes was designed. For library preparation we used SureSelect XT HS2 technology (Agilent Technologies) based on “target enrichment” with molecular barcodes. Sequencing was performed on a NovaSeq6000 (Illumina). Data were analyzed with the SureCall software (Agilent Technologies) with sensitivity of 1,0 % VAF. The detected variants were annotated using COSMIC, dbSNP, Ensembl and ClinVar. Selected variants were further monitored by dPCR (QIAcuity Digital PCR System; Qiagen) with sensitivity of 0,1 % VAF. Mutations were detected in 22/48 (46%) pts. The most frequently mutated genes were STAT6 (12/48 pts), TNFAIP3 (10/48 pts), XPO1 (7/48 pts), SOCS1 (7/26 pts). Frameshift deletions prevailed in TNFAIP3 and SOCS1 genes. Most mutations in the STAT6 (p.N417Y/D) and XPO1 (p.E571K) genes were hotspots. We monitored levels of these variants by dPCR during the course of disease and correlate results with clinical and PET-CT data. Fast, sensitive and noninvasive detection of mutations means an important improvement in diagnostics, prognostics, and monitoring of HL. NGS/dPCR approach would refine the evaluation of treatment response fundamentally. Correlation of mutational load with continuous PET examination would reduce the amount of false-positive results and enable us to use more precise and safe therapy de-escalation. DPCR proved to be sensitive, fast and afordable technology for MRD testing.
P063: Trial in Progress: Individualized Immunotherapy in Early-Stage Unfavorable Hodgkin Lymphoma - The Investigator-Initiated Phase II GHSG INDIE Trial
Authors: Paul J. Bröckelmann, Helen Kaul, Michael Fuchs, Carsten Kobe, Christian Baues, Peter Borchmann, Andreas Engert
Journal: HemaSphere (2022)

Figure 1: INDIE Trial Flowchart (Main Cohort age 18–60 years, N=100) Background: Immune-checkpoint blockade targeting the programmed cell death protein 1 (PD1) axis continue to reshape the therapeutic landscape of classical Hodgkin lymphoma (HL). The randomized phase II GHSG NIVAHL trial investigated nivolumab-based 1st-line treatment of early-stage unfavorable HL, either fully concomitant (4x nivo-AVD) or sequential (4x nivolumab, 2x nivo-AVD, 2x AVD) each followed by 30Gy involved-site radiotherapy (IS-RT; Bröckelmann PJ et al. JAMA Oncol 2020). The most recent update continued to show feasibility, a favorable safety profile and outstanding efficacy with 2-year progression-free (PFS) and overall survival (OS) of 99% and 100%, respectively (Bröckelmann PJ et al. ASH 2020). The upcoming GHSG phase II INDIE trial will investigate an individualized immunotherapy with the anti-PD1 antibody tislelizumab in this setting. Trial design: INDIE is an investigator-sponsored open-label phase II trial conducted at 35 GHSG trial sites in Germany. Patients with newly diagnosed early-stage unfavorable HL by GHSG criteria will receive two initial infusions of tislelizumab (200mg Q3W) followed by an FDG-PET/CT based restaging. Patients in complete metabolic remission will continue treatment with four additional tislelizumab infusions (300mg Q4W). Patients with residual metabolic activity will receive concomitant treatment with four cycles of AVD at standard dose and tislelizumab (300mg Q4W, tis-AVD). In the main cohort of N=100 patients aged 18–60 years, consolidative 30Gy IS-RT will only be applied in case of PET-positive residues (Figure 1). In an exploratory of N=20 patients >60 years of age, 30Gy IS-RT will be applied irrespective of remission status at end of systemic treatment. Primary endpoint is the 1-year PFS with 1- and 3-year OS, 3-year PFS, feasibility and safety, patient-reported outcomes and correlative studies being secondary endpoints. The trial is registered at clinicaltrials.gov (NCT04837859) and financially supported by BeiGene. Outlook: INDIE is the first trial to investigate an individualized immunotherapy in treatment naïve early-stage unfavorable HL, potentially omitting both chemo- and radiotherapy in optimally responding patients. Together with extensive correlative studies on longitudinal tumor biopsies, blood and stool samples, this trial will generate critical insights into response-adapted 1st-line HL immunotherapy.
P108: Integrating baseline circulating tumor DNA with interim PET improves outcome prediction in relapsed/refractory classical Hodgkin lymphoma
Authors: Eleonora Calabretta, Martina Di Trani, Martina Sollini, Francesca Ricci, Francesco Corrado, Vanessa Cristaldi, Stefanos Bonovas, Fabrizio Marino, Rita Mazza, Lodovico Terzi Di Bergamo, Alessio Bruscaggin, Maria Cristina Pirosa, Stefania Bramanti, Arturo Chiti, Armando Santoro, Davide Rossi, Carmelo Carlo-Stella
Journal: HemaSphere (2022)

Figure 1: Cumulative event rate of retreatment according to partitioning analysis categories. Background: Reliable biomarkers for early identification of treatment failure for relapsed/refractory (r/r) cHL are lacking. In this scenario, circulating tumor DNA (ctDNA) profiling may guide rational treatment choice. Aim: We performed a retrospective analysis in r/r cHL patients treated with the BEGEV regimen to assess the predictive efficacy of baseline ctDNA quantification. Additionally, we evaluated whether integrating ctDNA genotyping with interim positron emission tomography (iPET) may improve outcome prediction. Methods: 54 patients with r/r cHL treated with 4 cycles of BEGEV followed by autologous (auto) or allogeneic (allo) stem cell transplantation (SCT) were included in the study. Response was assessed by iPET after 2 cycles; complete response was defined as a Deauville Score (DS) of 1–3. Blood samples collected at baseline were profiled by CAPP-Seq. We performed partitioning analysis to evaluate the predictive value of baseline ctDNA load combined with iPET, assessed by need for further therapy within 18 months from BEGEV initiation. Results: In response to first-line therapy, 65% of patients were refractory. BEGEV was administered as second-line therapy in 61% of patients whereas 39% received BEGEV beyond second line. After induction, 54% of patients underwent auto-SCT and 24% proceeded to allo-SCT. The median baseline ctDNA value reported as haploid genome equivalent per ml (hGE/ml) was 39 (range, 4–5086), with ctDNA detected in PD patients being significantly higher as compared to CR patients (P=.0002). 31% of patients were iPET positive (DS 4/5), while 69% were negative. Baseline ctDNA predicted need for retreatment with an accuracy rate of 81% (sensitivity 63%, specificity 89%). iPET predicted the need for retreatment with similar accuracy rate (83%) and specificity (87%), but with a higher sensitivity (75%). Integrating baseline ctDNA and iPET resulted in an increased predictive value (accuracy rate 89%, sensitivity 75%, specificity 95%). Based on the results of the partitioning analysis, patients with positive iPET and high baseline ctDNA (>31 hGE/ml) showed a significantly inferior 18-months treatment-free survival with 92,3% (95% CI 84.9–99.7) of patients in this category requiring additional treatment (p<0.0001) (Fig 1). Conclusion: Patients with high baseline ctDNA and positive iPET have a limited benefit from completing the BEGEV regimen. Early switch to non-chemotherapeutic agents should be evaluated in prospective trials.
P041: Low percentage of T lymphocytes in Hodgkin’s Lymphoma lymph nodes, measured by flow cytometry, is associated with inferior progression free survival regardless of negative interim pet scan status
Authors: Laura Korin, Santiago Cranco, Lucia Fuente, Adriana Vitriu, Paola Ochoa, Evelina Babuin, Olivia Gelo, Luis Ayala, Andrea Novoa, Paula Tempra, Maria Belen Venegas, Anahi Vijnovich Baron, Norma Tartas, Rosario Custidiano, Cecilia Foncuberta, Julio Sanchez Avalos
Journal: HemaSphere (2022)

Figure 1: Kaplan-Meier estimates of progression free survival stratified according to T-lymphocyte percentage in lymph node biopsies in Hodgkin lymphoma Background: Tumor microenvironment (TME) can influence antitumor immunity and survival in Hodgkin lymphoma (HL) as previously published. However, most of this data has sparse clinical applicability. Flow cytometry (FC) has limited utility in HL diagnosis but its potential to assess TME has not been fully explored yet. Aims: To determine the prognostic impact on survival of the percentage (%) of tumor infiltrating lymphocytes (TIL) and CD4/CD8 ratio in lymph nodes (LN) measured by FC. Methods: We selected patients (pts) with HL, available LN FC data at diagnosis and i-PET scan, treated at our center from 2012–2020. FC was performed with 8-color panels according to Euroflow protocols. TIL % and CD4/CD8 ratio in LN by FC were compared to normal values reported (Battaglia, Immunology 2003) and stratified as low, normal and high. Response was assessed per Lugano recommendations. Progression free survival (PFS) was estimated with Kaplan-Meier, multivariate analysis with Cox regression, and variables were compared with log-rank test. Results: 46 pts were included. Median age: 34 years. 24/27 with early stage had unfavorable risk and 11/19 with advanced disease had IPS≥3. 95% received ABVD. Complete response rate was 91.3%. 2 pts died. Median PFS: not reached (NR), 75th percentile 43 months (m), and median follow up: 49 m. i-PET negative (neg) pts had significantly better PFS (median NR vs 13.7 m in i-PET positive subgroup, p:0.014). Low LN TIL % was associated with inferior PFS (median 24.4 m vs. NR in pts with normal or high TIL, p:0.024). Regarding CD4/CD8 ratio, PFS rates were 100%, 75% and 60% in normal, low and high subgroups respectively, p:0.041. Both low TIL and positive i-PET remained independent predictors of survival on multivariate analysis with HR of 11.8 (CI 95% 1.9–72.7, p:0.021), and 7.7 (CI 95% 1.6–36.4, p:0.01) respectively. LN TIL % could further stratify outcomes in pts with neg i-PET scans. In this subset, pts with low TIL had a median PFS of 24.4 m and PFS rates of 33.3% vs. median NR in normal and high subgroups and PFS rates of 88.9 and 87.5% respectively, p:0.006. Conclusions: LN TIL % measured by FC showed prognostic impact in our cohort of HL pts. Pts with low TIL had inferior PFS, even in those with optimal interim response where the median was only 2 years. This finding denotes the critical role of T cells to achieve cure. Checkpoint blockade might constitute an appealing approach in these pts to restore effective antitumor immunity.
P111: Phase I Trial of Brentuximab Vedotin plus Cyclosporine in Relapsed/Refractory Hodgkin Lymphoma
Authors: Swetha Kambhampati, Matthew Mei, Lu Chen, Sandrine Puvurel, Robert Chen, Leslie Popplewell, Liana Nikolaenko, Lacolle Peters, Saro Armenian, Larry Kwak, Steven T. Rosen, Stephen Forman, Alex F. Herrera
Journal: HemaSphere (2022)

Treatment of relapsed/refractory (R/R) Hodgkin lymphoma (HL) following failure of brentuximab vedotin (BV) and PD-1 blockade is a major unmet need. Resistance to BV is associated with multidrug resistance gene 1 (MDR1) overexpression. MDR1 inhibitors cyclosporine (CsA) or verapamil (VRP) can re-sensitize cHL to BV. We previously reported preliminary results of a phase I study of BV combined with CsA in R/R HL. Here we report the final results of the completed study. This is a single center, open-label phase I study. The dose finding portion followed a 3 + 3 design with 4 planned dose levels (DL). BV was given at 1.2 mg/kg (DL1) or 1.8 mg/kg (DL2-4) intravenously every 3 weeks. Planned dose of CsA was 5 mg/kg (DL1-2) or 7.5 mg/kg (DL3-4) orally twice daily on days 1–5. Planned dose of VRP was 120 mg orally four times daily on days 1–5 (DL4). Each cycle was 3 weeks. Once the maximum tolerated dose (MTD) was determined, BV-refractory pts were enrolled in an expansion cohort at the MTD. Primary objective was to determine the MTD and safety of the combination. Secondary objectives were overall response rate (ORR), complete response (CR) rate, response duration (DOR), overall survival (OS), and progression-free survival (PFS). 29 pts (14 dose-finding, 15 dose-expansion) were enrolled. Median age was 36 (20–69) and pts had a median of 5 (3–12) prior lines of therapy. All had prior BV (only 2 BV-sensitive) and 27 had prior PD-1 blockade. Four pts were treated on DL1, 22 on DL2, 3 on DL3. MTD was DL2. DLTs observed were: DL1 10-day CsA (n=1) grade (Gr) 3 hyperbilirubinemia, abdominal pain, and hypertension, DL2 (n=1) Gr3 abdominal pain and Gr3-4 neutropenia, DL3 (n=2) Gr3 bone pain/constipation/Gr4 lymphopenia (n=1) and Gr3 hyperglycemia (n=1). Median duration of treatment was 3 (1–16) cycles. Most frequent adverse events (AEs) were nausea (90%), hypertension (90%), anemia (86%), fatigue (76%), neutropenia (76%), and leukopenia (76%). All pts had Gr3+ AEs with most frequent being neutropenia (62%). Reasons for treatment discontinuation included death (n=4), disease progression (n=10), and toxicity (n=2). Treatment-related death occurred in 3 pts (pneumonitis at DL1, respiratory failure and hypotension at DL2). The ORR/CR was 62%/24%. The median DOR and PFS was 5 months and median OS was not reached. BV + CsA was effective in BV-refractory R/R HL but was also associated with toxicity leading to early study termination.
P060: Prognosis of patients with relapsed and refractory classic Hodgkin lymphoma after nivolumab discontinuation and efficacy of nivolumab retreatment
Authors: Liudmila Fedorova, Kirill Lepik, Natalia Mikhailova, Elena Kondakova, Yaroslava Komarova, Polina Kotselyabina, Evgenia Borzenkova, Vadim Baykov, Ivan Moiseev, Alexander Kulagin
Journal: HemaSphere (2022)

Table 1: Patient’s characteristics Background: The optimal nivolumab (N) therapy duration for patients (pts) with relapsed and refractory classic Hodgkin lymphoma (r/r cHL) has not been determined and this question remains a pressing issue. The possibility of prolonged remission after treatment discontinuation in complete response (CR) as well as the preservation of sensitivity to PD-1 inhibitors retreatment was previously demonstrated. However as the number of report regarding the problem of N discontinuation and retreatment is limited, the accumulation of additional data is required. Aims: To analyze the survival of pts with r/r cHL after N discontinuation as well as the efficacy and safety of N retreatment. Methods: The retrospective analysis included 48 pts with r/r cHL who were treated with N 3 mg/kg (n=29) or 40 mg (n=19). All pts discontinued N due to different reasons in CR (n=40) or partial response (PR) (n=8). In case of disease relapse the PD-1 inhibitors monotherapy was reinitiated. The response was evaluated by PET-CT using LYRIC criteria. Adverse events (AE) were analyzed by NCI CTCAE 4.0.3. In group of N discontinuation PFS, OS were evaluated. In group of N retreatment ORR, PFS, OS and AE rate were also analyzed. PFS estimates was censored by the time of additional therapy initiation in group of N retreatment. Results: Patient’s characteristics are demonstrated in the table 1. Reasons for N discontinuation were: grade 3–4 AE in 6 (13%) pts, Russian nivolumab NPP discontinuation in 27 (56%), patient’s decision in 15 (31%). Median follow up was 48 (4–65) mo. Disease relapse was occurred in 30 (63%) pts. Median PFS in group of patients who achieved CR was 24 mo (95%CI: 11.7-NA) and 4-y PFS was 43.6% (95%CI: 26.9–58.3), in group of PR all patients had disease progression: median PFS was 7.7 mo (95% CI: 5.6–16.5). Only 1 pt died due to progressive multifocal leukoencephalopathy after allo-HSCT. Median OS was not reached, 4-y OS was 92.9% (95%CI: 59.1–99). Retreatment with mono-N was initiated in 22 pts. Median follow up was 33 (7–56) mo. ORR was 73%: CR was achieved in 9 (41%) pts, PR in 7 (32%), indeterminate response in 6 (27%). Median PFS was 24.8 mo (95%CI: 17.2-NA), 3-y PFS 26.7% (95%CI: 7.5–51). Nine (41%) pts demonstrated AE during N retreatment, 4 (18%) pts - grade 3–4 AE. Conclusion: Patients with r/r cHL who achieved CR after N therapy may demonstrate durable remissions after N discontinuation. In case of disease relapse N retreatment is effective and safe option.
P105: Decisional role of interim PET in relapsed/refractory classical Hodgkin Lymphoma treated with four begev cycles
Authors: Chiara Rusconi, Francesca Ricci, Vittorio R. Zilioli, Vincenzo Marasco, Eleonora Calabretta, Anna Guidetti, Cristina Muzi, Federico Mazzon, Margherita Smania, Martina Sollini, Erika Meli, Marcello Rodari, Emanuele Ravano, Roberto Cairoli, Paolo Corradini, Armando Santoro
Journal: HemaSphere (2022)

Figure 1: Event-free survival according to PET2 result Achievement of complete response (CR) before autologous stem cell transplantation (ASCT) is one of the main predictive factors of outcome in patients (pts) affected by relapsed/refractory (R/R) classical Hodgkin Lymphoma (cHL) eligible to high-dose chemotherapy. The predictive role of interim PET during salvage treatment has not been investigated in pts receiving BEGEV (Bendamustine, Gemcitabine and Vinorelbine) as first salvage treatment. With the aim to investigate the predictive value of PET after 2 cycles of BEGEV (PET2) in terms of CR rate and survival in pts who completed 4 BEGEV courses followed by ASCT, we retrospectively collected data of 90 consecutive R/R cHL pts eligible to ASCT treated from 2011 to 2021 in 3 Italian centres. Eleven out of 90 pts were excluded due to BEGEV discontinuation for progressive disease (PD) before or at PET2. Seventy-nine pts who completed the planned 4 BEGEV cycles were analysed: median age at relapse was 37 years (range: 18–70), 39 pts (49%) were in stage III-IV, 13 pts (16%) had B symptoms and 23 pts (29%) had extranodal involvement (EI). Thirty-eight pts (48%) were primary refractory, 21 pts (27%) had an early and 20 pts (25%) a late relapse. PET2 was negative [Deauville Score (DS) 1–3] in 61 (77%) and positive in 18 pts (23%) (DS 4 in 15 pts, DS 5 in 3 pts). Adverse risk factors at relapse (EI, B symptoms and time to relapse) did not correlate with PET2 positivity. At evaluation after 4 BEGEV cycles, CR was achieved in 62 (78%), partial response in 6 (8%) and PD in 11 (14%) pts. Complete response after 4 BEGEV was obtained in 55/61 (90%) PET2 negative pts and 7/18 (39%) PET2 positive pts (OR=14.4, 95% CI 3.8–45.2, p<0.0001). Autologous SCT was performed in 73 pts, following BEGEV in 59 pts (75%) and after further salvage treatments in 14 pts (18%). With a median follow-up of 36 (range: 5–100) months, 3-years overall survival (OS), progression-free survival (PFS) and event-free survival (EFS) for the whole study population were 93%, 72% and 63%. No significant differences in OS and PFS were detected according to PET2 result. Conversely, 3-years EFS was significantly superior in PET2 negative vs PET2 positive pts [71% vs 32%, OR 13.66 (95% CI 3.4–62.1) p<0.0001] (Fig.1). In conclusion, R/R cHL pts with PET2 positive during BEGEV salvage treatment had a significantly inferior probability to achieve CR after 2 additional BEGEV cycles and could benefit from early exposure to new therapeutic strategies before ASCT.
P010: Inferior Outcomes for Young Adults Treated on Advanced Stage Clinical Trials: Report from the HoLISTIC Consortium
Authors: Susan K. Parsons, Angie Mae Rodday, Jonathan W. Friedberg, Andrea Gallamini, Eliza Hawkes, David Hodgson, Peter Johnson, Brian Link, Matthew Maurer, Jason Nelson, Kerry J. Savage, Jenica Upshaw, Pier Luigi Zinzani, Andrew M. Evens
Journal: HemaSphere (2022)

Figure 1: Relationship Between Age and Risk of Progression and Death (n=3893). Background: Inferior outcomes have been reported for adolescents and young adults (AYAs) across several cancer types, as compared to younger pediatric or older patients (pts). While lack of access to clinical trials has been implicated, we described inferior outcomes for AYAs treated on a large US Hodgkin Lymphoma (HL) adult study (Henderson, 2018). Earlier this year, in an analysis of three US phase 3 pediatric HL trials, worse outcomes were reported for pts >15 years (yrs) compared with younger pts (Kahn, 2022). Little is known about the impact of age on outcomes from recent adult clinical trials. Methods: Individual patient data from eight advanced stage clinical trials (ECOG2496, SWOG0816, HD2000, HD9601, HD0607, HD0801, UK Stanford V, and RATHL), conducted from 1996–2012, were harmonized as part of the HoLISTIC Consortium. Pts with classic HL, stage IIb, III or IV disease, ages 14–65 yrs, and treated at adult centers were included. Outcomes were 5-yr progression-free survival (PFS) and 5-yr overall survival (OS), which were estimated in univariable and multivariable models. Age at diagnosis and 10 other clinical factors, were examined with multivariable adjusted plots and piecewise linear splines to identify functional forms of the relationship with PFS or OS. Multiple imputation was used for missing data. Results: Data on 3893 HL patients were included. Across all studies, 5-year PFS was 76.5% (95% CI=75.1%, 77.9%); 5-year OS was 91.6% (95% CI=90.7%, 92.6%). Median age was 32 yrs and 41% of patients were <30 yrs at diagnosis. Associations between age (analyzed as a continuous variable) and PFS displayed a distinct piecewise linear relationship with an inflection point at age 30 (Figure A). In multivariable analyses, PFS improved from ages 14 to 30, and then declined after age 30 (Figure B). The association between age and OS was not significant <30 yrs, advancing age >30 yrs was associated with worse OS. These patterns were seen broadly across studies and not dominated by one trial. Conclusion: The association between age and HL survival in the modern era appears to be more nuanced than the dichotomous variable of age at 45 yrs, as used in previous models. While patients under 30 yrs have worse short-term disease outcomes than age 30 yrs, 5-yr OS results suggest that younger patients may be amenable to successful salvage. Further research is needed to understand these differences to optimize outcomes.